P741: DDX41 MUTATIONS DEFINE A UNIQUE SUBTYPE OF MYELOID NEOPLASMS.
Authors: H. Makishima, R. Saiki, Y. Nannya, S. Korotev, C. Gurnari, J. Takeda, Y. Momozawa, S. Best, P. Krishnamurthy, T. Yoshizato, Y. Atsuta, Y. Shiozawa, Y. Iijima-Yamashita, K. Yoshida, Y. Shiraishi, Y. Nagata, N. Kakiuchi, M. Onizuka, K. Chiba, H. Tanaka, A. Kon, Y. Ochi, M. Nakagawa, R. Okuda, T. Mori, H. Itonaga, Y. Miyazaki, M. Sanada, H. Tsurumi, S. Kasahara, C. Müller-Tidow, A. Takaori-Kondo, K. Ohyashiki, T. Kiguchi, F. Matsuda, J. Jansen, C. Polprasert, S. Miyano, L. Malcovati, T. Haferlach, M. Kubo, M. Cazzola, A. Kulasekararaj, L. Godley, J. Maciejewski, S. Ogawa
Journal: HemaSphere (2022)

Background:DDX41 was identified as a causative gene for late-onset familial myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). While DDX41 is thought to be one of the most frequent targets of germline mutations responsible for sporadic cases with AML/MDS and other myeloid neoplasms (MN), the entire spectrum of pathogenic DDX41 variants and their effect size therein are still to be elucidated. The clinical and genetic pictures of DDX41-mutated myeloid neoplasms have not fully been investigated in a large cohort of patients, either. Aims: In this study, we enrolled a total of 9,081 sporadic and familial cases with different MNs from different ethnicities, in which germline and somatic mutations in DDX41 and other major driver genes in AML/MDS were analyzed using next generation sequencing. Methods: To estimate the size of the risk of MN development associated with pathogenic germline DDX41 variants, we calculated their enrichment in 3,672 MN cases as compared with a control cohort (n=20,238). We also estimated the penetrance of pathogenic DDX41 germline variants for the development of MNs. Results: We identified 292 cases with pathogenic or likely pathogenic DDX41 mutations with conspicuous ethnic diversity, of which 159 (54%) accompanied somatic mutations as well, while the remaining 53 cases had somatic mutations alone. Among 292 germline variants, 197 were truncating variants, whereas only 2.6% of somatic mutations were truncating (P<0.0001). Pathogenic germline mutations were significantly more frequent in Asian than in Caucasian cases (odds ratio (OR)=1.64), consistent with a significantly higher frequency of pathogenic germline DDX41 variants in the former cases. We observed a significant enrichment of 5 DDX41 variants in myeloid neoplasms, including p.A500fs, p.E7*, p.Y259C, p.E256K, and p.S363del, compared with 20,238 control cases, with a mean odds ratio of 10.6. To estimate the penetrance of NMs associated with pathogenic germline variants, we calculated cumulative incidence of MN in a cohort of 384 first-degree relatives (kin-cohort) of DDX41-mutated NM cases. Penetrance of pathogenic DDX41 germline variants was only negligible under 40 years of age, but rapidly elevated thereafter, reaching as high as 38.5% at the age of 85, confirming late onset of DDX41-mutated MNs. DDX41 variants were significantly more common in higher risk MDS (7.1%) and secondary AML (9.7%), compared with other myeloid neoplasms (1.9%). Patients with MDS having both germline and somatic mutations were more likely to classified in refractory anemia with excess blasts (RAEB), compared with those with germline or somatic alone (P=0.029). DDX41 variants were significantly associated with lower WBC and hypocellular bone marrow. Most frequently co-occurring mutations included those in ASXL1, SRSF2, TET2, CUX1, and DNMT3A, of which only CUX1 mutations were statistically significant. Among MDS cases, DDX41 mutations were associated with a significantly higher incidence of leukemic evolution (P=0.006) than DDX41-unmutated cases, which was virtually confined to those with truncating DDX41 variants. However, despite this, DDX41-mutated cases had a better OS than un-mutated cases, particularly when treated with hypomethylating agents (HMAs) (P<0.001). Summary/Conclusion: In summary, DDX41-mutated myeloid neoplasms define a distinct entity of myelodysplasias associated with higher incidence of leukemic evolution and better responsiveness to hypomethylating agents.